Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers.
To investigate the pharmacokinetic/pharmacodynamic interactions of the antidiabetic agents canagliflozin (a sodium-glucose cotransporter-2 inhibitor) and teneligliptin (a dipeptidyl peptidase-4 inhibitor) in Japanese healthy adult men. Open-label, one-way crossover study used canagliflozin (200 mg/day p.o.) and teneligliptin (40mg/day p.o). A single dose of object drug (either canagliflozin or teneligliptin) was administered on day 1 followed by washout and continuous administration of precipitant drug (days 1 - 9). Both drugs were concomitantly administered on day 7. No changes in AUC0 - 72h and Cmax were observed for canagliflozin+teneligliptin versus monotherapy; geometric mean ratios for AUC0 - 72h and Cmax were 0.982 and 0.982 for the plasma concentration of canagliflozin and 0.983 and 0.976 for the plasma concentration of teneligliptin, respectively. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) increased with canagliflozin+teneligliptin versus teneligliptin alone. Mean AUC0.5 - 4h increased post-meal, on combination therapy, from 9.6 to 12.5 pmol·h/l (active GLP-1) and from 21.5 to 32.3 pmol·h/l (total GLP-1). Adverse events developed in four subjects; all were mild and resolved but one subject withdrew due to generalized erythema. GLP-1 levels increased with the canagliflozin+teneligliptin combination, and no PK interaction was observed. This combination may show favorable antidiabetic effects without increasing systemic exposure.


Evolution of endocrine adjuvant therapy for early breast cancer.
Endocrine treatment plays a pivotal role in the adjuvant therapy of patients harbouring oestrogen and/or progesterone receptor positive breast cancer. The objective of this paper is to critically review endocrine treatment options in early breast cancer focusing on ongoing development. Literature was collected through the ISI Web of Science and PubMed in January/February 2009 with subsequent update by December 2009, using the words breast cancer, endocrine therapy, oestrogen receptor and aromatase. Endocrine therapy improves outcome in early breast cancer. Yet several controversies remain. There has recently been a lack of general consensus regarding the limit of oestrogen receptor positivity. As for adjuvant therapy in general and use of aromatase inhibitors in particular, we need the results from ongoing studies to decide what may be the optimal duration of therapy and regimen (sequential treatment versus monotherapy; one drug compared with another). Further, there is a need to critically assess optimal use of endocrine therapy for metastatic disease among patients previously exposed to endocrine regimens in the adjuvant setting. While in general the mechanisms of resistance to endocrine therapy among ER positive tumours remains unknown, merging evidence suggest a role of different growth factor pathways, in particular HER-2 activation. Thus, particular attention is paid to the topic of HER-2 expression as a potential cause of endocrine resistance.


TAMIS-Flap Technique: Full-thickness Advancement Rectal Flap for High Perianal Fistulae Performed Through Transanal Minimally Invasive Surgery.
The formation of an advancement rectal flap could be technically demanding in the presence of high perianal of rectovaginal fistula, and the outcomes could be frustrated by the inadequate view, bleeding and a poor exposure through the standard transanal approach. The application of the transanal minimally invasive surgery (TAMIS) to the advancement rectal flap procedure could overcome these difficulties. In the lithotomy position, a partial fistulectomy was performed and the internal opening was closed. A full-thickness flap was mobilized initially through the classic transanal approach. Subsequently, the TAMIS port was inserted and the mobilization of the flap was carried on proximally for as long as required. The laparoscopic visualization allowed a perfect view, a proper orientation of the flap and accurate hemostasis. The TAMIS-flap procedure seems a promising technique to perform a long advancement rectal flap to treat high perianal or rectovaginal fistulae (Video, Supplemental Digital Content 1, http://links.lww.com/SLE/A208).


The size control of silver nanocrystals with different polyols and its application to low-reflection coating materials.
The size of silver nanocrystals in polyol synthesis can be simply controlled by tuning the viscosity of the reaction medium such as ethylene glycol, 1,2-propanediol, 1,4-butanediol and 1,5-pentanediol. We found that a higher viscose medium (1,5-pentanediol) led to monodispersed smaller particles thanks to the slow addition of silver atoms into the nuclei. Size-controlled silver nanocrystals of 30 nm were obtained in a viscosity controlled medium of 1,5-pentanediol to synthesize a low refractive index filler by coating with silica and subsequent etching of the silver core. The coated low-reflection layer from the hollow silica nanoparticles on polyethylene terephthalate (PET) film can greatly reduce the reflection of the PET film from 10% to 2% over the entire visible region.


Ultrafast Fluorescence Dynamics in Flurbiprofen-Amino Acid Dyads and in the Supramolecular Drug/Protein Complex.
The interaction dynamics between the drug flurbiprofen (FBP) and human serum albumin (HSA) has been investigated by time-resolved fluorescence spectroscopy, combining femtosecond fluorescence upconversion and picosecond time-correlated single photon counting. In order to obtain additional information on the drug/ protein interaction, several covalently linked model dyads, composed of FBP and tryptophan or tyrosine, were also studied. For all systems, the main feature was a remarkable dynamic FBP fluorescence quenching, more prominent in the dyads than in the protein complex. All systems also displayed a clear stereoselectivity depending on the (S)- or (R)-form of FBP, that was strongly influenced by the conformational arrangement of the investigated chromophores.


Bendopnea Predicts Right Ventricular Energy Failure in Patients with Pulmonary Hypertension.
The development of right ventricular failure has a significant adverse prognostic impact on the course of pulmonary hypertension. Right ventricular energy failure has been shown to double the mortality of pulmonary hypertension even after correction for many established risk predictors. We hypothesize that bendopnea may indicate right ventricular energy failure in patients with pulmonary hypertension. We prospectively enrolled patients with pulmonary hypertension who were admitted to our pulmonary hypertension outpatient clinic between January 2021 and June 2021. Bendopnea was assessed by asking patients to bend forward and report any shortness of breath within 30 seconds. Routine physical examination, laboratory tests, echocardiography, and right heart catheterization parameters were collected. A total of 167 patients were enrolled into the study. Bendopnea and right ventricular energy failure was present in 79 (47.3%) and 43 (25.7%) patients, respectively. Bendopnea accurately predicted the presence of right ventricular energy failure (area under the curve, 0.667; 95% CI, 0.574-0.760; P < 0.001) and had a significantly superior diagnostic power compared with many other symptoms and signs. Our study shows that bendopnea predicts right ventricular energy failure in patients with pulmonary hypertension and can be added to our physical examination armamentarium as an easy, rapid, and noninvasive prognostic tool.


Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Objective: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. Methods: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. Conclusion: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.


Emerging laser-assisted vacuum processes for ultra-precision, high-yield manufacturing.
Laser technology is a cutting-edge process with a unique photothermal response, precise site selectivity, and remote controllability. Laser technology has recently emerged as a novel tool in the semiconductor, display, and thin film industries by providing additional capabilities to existing high-vacuum equipment. The in situ and in operando laser assistance enables using multiple process environments with a level of complexity unachievable with conventional vacuum equipment. This broadens the usable range of process parameters and directly improves material properties, product precision, and device performance. This review paper examines the recent research trends in laser-assisted vacuum processes (LAVPs) as a vital tool for innovation in next-generation manufacturing processing equipment and addresses the unique characteristics and mechanisms of lasers exclusively used in each study. All the findings suggest that the LAVP can lead to methodological breakthroughs in dry etching, 2D material synthesis, and chemical vapor deposition for optoelectronic devices.


Avian Podocytes, Which Lack Nephrin, Use Adherens Junction Proteins at Intercellular Junctions.
Nephrin, a major intercellular junction (ICJ) molecule of mammalian podocytes in the renal glomerulus, is absent in the avian genome. We hypothesized that birds use ICJ molecules other than nephrin in their podocytes. Therefore, in the present study, we examined the possible involvement of adherens junction (AJ) proteins in the ICJs of avian podocytes. We found the AJ proteins N-cadherin and α- and β-catenins in podocytes of quail and chickens but not in those of rats, pigs or humans. The AJ proteins were prominent in avian glomerulus-rich fractions in immunoblot analyses, and in immunofluorescence microscopy analyses, they were localized along glomerular capillary walls appearing in at least two staining patterns: weakly diffuse and distinctly granular. Immunoelectron microscopy demonstrated that the significant accumulation of immunogold particles for the AJ proteins were especially evident in avian slit diaphragms and AJs. Furthermore, N-cadherin was found to be expressed in all nephron cells in the early developmental stage but became confined to podocytes during maturation. These results indicate that avian slit diaphragms clearly express AJ proteins as compared with that in the mammal-where AJ proteins are suppressed to an extremely low level-and that avian podocytes are interconnected by AJs per se in addition to slit diaphragms.


Heterologous co-expression of a yeast diacylglycerol acyltransferase (ScDGA1) and a plant oleosin (AtOLEO3) as an efficient tool for enhancing triacylglycerol accumulation in the marine diatom Phaeodactylum tricornutum.
Microalgae are promising alternate and renewable sources for producing valuable products such as biofuel and essential fatty acids. Although this is the case, there are still challenges impeding on the effective commercial production of microalgal products. For instance, their product yield is still too low. Therefore, this study was oriented towards enhancing triacylglycerol (TAG) accumulation in the diatom Phaeodactylum tricornutum (strain Pt4). To achieve this, a type 2 acyl-CoA:diacylglycerol acyltransferase from yeast (ScDGA1) and the lipid droplet (LD) stabilizing oleosin protein 3 from Arabidopsis thaliana (AtOLEO3) were expressed in Pt4. The individual expression of ScDGA1 and AtOLEO3 in Pt4 resulted in a 2.3- and 1.4-fold increase in TAG levels, respectively, in comparison to the wild type. The co-expression of both, ScDGA1 and AtOLEO3, was accompanied by a 3.6-fold increase in TAG content. On the cellular level, the lines co-expressing ScDGA1 and AtOLEO3 showed the presence of the larger and increased numbers of lipid droplets when compared to transformants expressing single genes and an empty vector. Under nitrogen stress, TAG productivity was further increased twofold in comparison to nitrogen-replete conditions. While TAG accumulation was enhanced in the analyzed transformants, the fatty acid composition remained unchanged neither in the total lipid nor in the TAG profile. The co-expression of two genes was shown to be a more effective strategy for enhancing TAG accumulation in P. tricornutum strain Pt4 than a single gene strategy. For the first time in a diatom, a LD protein from a vascular plant, oleosin, was shown to have an impact on TAG accumulation and on LD organization.


The effects of neuregulin1 on brain function in controls and patients with schizophrenia and bipolar disorder.
Recent studies have identified neuregulin1 as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders. The present investigation examined the impact of neuregulin1 genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 115 subjects comprising 41 patients with schizophrenia, 29 patients with bipolar disorder and 45 healthy volunteers. We then used statistical parametric mapping to estimate the main effects of diagnostic group, the main effect of genotype and their interaction. We tested the hypothesis that the high-risk variant of neuregulin1 would be associated with altered prefrontal function. In all three diagnostic groups, the high-risk variant of neuregulin1 was associated with greater deactivation in the left precuneus. In addition, there was an interaction between diagnosis and genotype in two regions of the prefrontal cortex. The right inferior frontal gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with schizophrenia. Conversely, the right posterior orbital gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with bipolar disorder. Our results suggest that genetic variation in neuregulin1 has a measurable impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in different regions of the prefrontal cortex.


Penning Ionization of Acene Molecules by Helium Nanodroplets.
Acene molecules (anthracene, tetracene, pentacene) and fullerene (C60) are embedded in He nanodroplets (HeN) and probed by EUV synchrotron radiation. When resonantly exciting the He nanodroplets, the embedded molecules M are efficiently ionized by the Penning reaction HeN* + M → HeN + M+ + e-. However, the Penning electron spectra are all broad and structureless, largely differing from those measured by binary Penning collisions, as well as from those measured for dopants bound to the He droplet surface. Simulations based on elastic binary electron-He collisions qualitatively reproduce the measured spectra only when assuming unexpectedly large He droplets, indicating that electron spectra of molecules embedded in helium nanodroplets are severely affected by collective electron-helium interactions.


Perception and attitude about systemic health and periodontal disease among dentistry undergraduates.
To evaluate the perceptions held by dentistry undergraduates about the relationship between general health and periodontal disease. In addition, student knowledge about treatment of patients with systemic disorders was also examined. Participants were all undergraduates in the last year of dental school from three different universities (N = 253). Inclusion criteria were students enrolled in their last year of the dental curriculum and who agreed to participate in the research. After the participants filled out a structured questionnaire, the results were analysed using Epi Info 3.5.1 software and the chi-square, Friedman and Wilcoxon tests. The majority of participants recognised the relationship between periodontal and cardiac disease and diabetes mellitus. However, only half of the participants were aware of the relationship between periodontal disease and stroke (50.5%). In relation to caring for patients with systemic diseases, 61.4% of students surveyed did not know the blood glucose level that characterises a hypoglycemic status. The majority of participants (61.8%) stated the importance of evaluating vital signs prior to dental treatment. However, only 13.3% of the participants included temperature and respiratory rate as vital signs. The perception and attitude of undergraduates about the items on the questionnaire were deficient. Thus, a more holistic view of the patient is warranted within dental education, promoting health and quality of life.


Giant posterior mediastinal liposarcoma invading the esophagus: a case report.
Giant liposarcoma is an unusual variant of mediastinal tumors. The case of a 73-year-old woman is reported. She presented with a posterior mediastinal tumor invading the third middle tract of the thoracic esophagus and the adventitia of the descending aorta, close to the posterior pericardium; a neoplastic thrombus 2cm in size was located in the upper left pulmonary vein. The tumor was completely excised by left thoracotomy, in extracorporeal circulation. The postoperative course was uneventful and the patient received adjuvant chemotherapy. She is currently alive after 8 months, disease-free. The natural history, pathology, and prognosis of the disease are reviewed and management of such lesions is discussed.


Comparing morphological plasticity of root orders in slow- and fast-growing citrus rootstocks supplied with different nitrate levels.
Studies of the plasticity of functional root traits involved in resource acquisition have focused mainly on root length without considering such 'morphological components' as biomass allocation, specific root length, root fineness, and tissue density that affect root length. The plasticity of the above components in response to nitrate supply was studied in each root order of two co-generic citrus rootstocks, namely the fast-growing Citrus jambhiri 'Rough Lemon' (RL) and the slow-growing Citrus reshni 'Cleopatra Mandarin' (CM). Morphological traits of individual root orders of CM and RL, grown at different nitrate levels (NO(3)-N at 0.1, 0.5, 1 and 10 mm) were examined by using an image-specific analysis system. At high nitrate levels, the root length ratio, root mass ratio and, to a lesser degree, specific root length, root fineness and tissue density of tap and 1st-order laterals in both CM and RL were reduced. In 2nd-order laterals, however, the same treatment led to increased values of each morphological trait in CM but decreased values of the same traits in RL. At low nitrate supply, CM exhibited longer tap roots whereas RL developed longer 2nd-order laterals. These effects were due to root mass ratio and, to a lesser extent, specific root length. Biomass allocation was the main component of nitrate-induced changes in root length ratio. The 2nd-order laterals were more sensitive to nitrate availability than the tap root and 1st-order laterals. At low nitrate availability, RL displayed longer 2nd-order lateral roots and lower root plasticity than CM. This suggests a different root growth strategy among citrus rootstocks for adapting to nitrate availability: RL invests in 2nd-order laterals, the preferred zone for acquiring the nutrient, whereas CM responds with longer tap roots.


Simultaneous determination of savaside A, acteoside, and isoacteoside in rat plasma by UHPLC-MS/MS: Comparative pharmacokinetic and bioavailability characteristics of Monochasma savatieri via different routes of administration.
Phenylethanoid glycosides are the bioactive components in Monochasma savatieri that primarily contains savaside A, acteoside, and isoacteoside. Pharmacological research has been comprehensive, but there have been few studies on pharmacokinetics, especially about savaside A. An ultra high performance liquid chromatography with tandem mass spectrometry with multiple reaction monitoring mode was developed and validated for the simultaneous determination of the three compounds from M. savatieri. Meanwhile, this method was fully validated and successfully applied to compare the pharmacokinetics and bioavailability following four different routes included intravenous injection, intraperitoneal injection, muscle injection, and oral administration. The results indicated that the three compounds could be rapidly absorbed within 1 h, and the main pharmacokinetic parameters showed significant differences (P < 0.05). The bioavailability of oral administration, intramuscular injection, and intraperitoneal injection did not exceed 0.2, 25, and 10%, respectively. Comparing the bioavailability, it exhibited that acteoside > isoacteoside > savaside A following the four administration routes. Notably, the isomerization position of acteoside and isoacteoside mainly occurred in the liver according to the pharmacokinetics profiles of intraperitoneal and intravenous injection, in addition, isoacteoside exhibited more structural selectivity than acteoside in vivo. It demonstrated that three compounds undergo different processes, mainly affected by the first-pass effect and their intestinal stability is extremely poor.


The Central-Splitting Approach for Achilles Insertional Tendinopathy and Haglund Deformity.
Insertional Achilles tendinopathy causes posterior heel pain at the insertion of the Achilles tendon, often in combination with a calcaneal exostosis, or Haglund deformity. Insertional Achilles tendinopathy often presents with a posterior osseous prominence and leads to calcification of the Achilles tendon1. Nonoperative treatment of these conditions includes activity modification, nonsteroidal anti-inflammatory agents, heel lifts, shoe modification, physical therapy focused on eccentric strengthening exercises, iontophoresis, and shock wave therapy. Nonoperative treatment will fail in approximately 50% of these cases, and such patients become candidates for surgical intervention2,3. Multiple surgical approaches have been described, including the medial J-shaped, lateral, Cincinnati transverse, double incision, and central-splitting approaches4. Currently, there is no consensus regarding the ideal approach. Recent literature has suggested that the central-splitting approach allows for adequate exposure of both the most commonly diseased area of the tendon and the calcaneal exostosis, with excellent postoperative pain and functional results5-13. Place the patient in the prone position with the feet at the edge of the operating table. Make a full-thickness, 5 to 7-cm longitudinal incision centered over the Achilles tendon and the posterior aspect of the calcaneus. Make a central incision through the Achilles tendon. Sharply mobilize the medial and lateral slips and excise the diseased portion of the Achilles tendon. Expose the calcaneal exostosis and perform the calcaneal exostectomy with a microsagittal saw. Repair the remaining healthy-appearing Achilles tendon to the calcaneus with 2 suture anchors. An additional suture anchor or, alternatively, the double-row technique for the Achilles tendon repair may be used. Repair the central split in the Achilles tendon with absorbable suture. Close the soft tissue and skin in layers. Alternative approaches include the medial, lateral, or Cincinnati transverse incisions. The central-splitting approach is favored because of the excellent exposure of both the diseased tendon and the calcaneal exostosis. Additional augmentations to this procedure include a flexor hallucis longus transfer and a gastrocnemius recession. This technique provides adequate exposure to the diseased Achilles tendon, calcific deposits, and calcaneal exostosis. Recent studies have demonstrated it to be a safe and effective technique with high patient-satisfaction scores5-13.


Cord around the neck: should it be severed at delivery? A randomized controlled study.
Umbilical cords often become encircled around portions of the fetus, usually the neck. The incidence ranges from 21% in one loop to 0.2% in three loops. In the present study, we assessed the practice of severing the cord, which was encircled once around the neck of the fetus, after delivery of the anterior shoulder and prior to extraction of the body. This was a prospective, randomized, controlled study. The study and the control groups included 30 women each. Cord around the neck was diagnosed during labor by ultrasound. It was cut intentionally in the study group and left intact in the control group. Demographic data were obtained. The course of labor was assessed. Neonatal outcomes measured were cord pH, Apgar scores at 5 minutes, and need for resuscitation. Length of maternal and neonatal hospitalization was determined. No differences were found between the study and the control group before, during, and after labor regarding perinatal variables such as meconium-stained amniotic fluid, fetal heart rate patterns, Apgar scores at 5 minutes, and umbilical cord pH after delivery (7.29 +/- 0.07 [SD] in the study group and 7.32 +/- 0.06 [SD] in the controls; p=0.1). Single nuchal encirclement by the umbilical cord during labor, after delivery of the anterior shoulder, can be severed or left intact. We could not detect any adverse perinatal outcome in such deliveries.


Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways.
The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and PKC signaling. Defective membrane transfer from PMNs to MNCs in patients with active systemic lupus erythematous suppressed activated mononuclear IL-2 production.


Integrating pediatric TB services into child healthcare services in Africa: study protocol for the INPUT cluster-randomized stepped wedge trial.
Tuberculosis is among the top-10 causes of mortality in children with more than 1 million children suffering from TB disease annually worldwide. The main challenge in young children is the difficulty in establishing an accurate diagnosis of active TB. The INPUT study is a stepped-wedge cluster-randomized intervention study aiming to assess the effectiveness of integrating TB services into child healthcare services on TB diagnosis capacities in children under 5 years of age. Two strategies will be compared: i) The standard of care, offering pediatric TB services based on national standard of care; ii) The intervention, with pediatric TB services integrated into child healthcare services: it consists of a package of training, supportive supervision, job aids, and logistical support to the integration of TB screening and diagnosis activities into pediatric services. The design is a cluster-randomized stepped-wedge of 12 study clusters in Cameroon and Kenya. The sites start enrolling participants under standard-of-care and will transition to the intervention at randomly assigned time points. We enroll children aged less than 5 years with a presumptive diagnosis of TB after obtaining caregiver written informed consent. The participants are followed through TB diagnosis and treatment, with clinical information prospectively abstracted from their medical records. The primary outcome is the proportion of TB cases diagnosed among children < 5 years old attending the child healthcare services. Secondary outcomes include: number of children screened for presumptive active TB; diagnosed; initiated on TB treatment; and completing treatment. We will also assess the cost-effectiveness of the intervention, its acceptability among health care providers and users, and fidelity of implementation. Study enrolments started in May 2019, enrolments will be completed in October 2020 and follow up will be completed by June 2021. The study findings will be disseminated to national, regional and international audiences and will inform innovative approaches to integration of TB screening, diagnosis, and treatment initiation into child health care services. NCT03862261, initial release 12 February 2019.


Exploring the evolution of a trade-off between vigilance and foraging in group-living organisms.
Even though grouping behaviour has been actively studied for over a century, the relative importance of the numerous proposed fitness benefits of grouping remain unclear. We use a digital model of evolving prey under simulated predation to directly explore the evolution of gregarious foraging behaviour according to one such benefit, the 'many eyes' hypothesis. According to this hypothesis, collective vigilance allows prey in large groups to detect predators more efficiently by making alarm signals or behavioural cues to each other, thereby allowing individuals within the group to spend more time foraging. Here, we find that collective vigilance is sufficient to select for gregarious foraging behaviour as long there is not a direct cost for grouping (e.g. competition for limited food resources), even when controlling for confounding factors such as the dilution effect. Furthermore, we explore the role of the genetic relatedness and reproductive strategy of the prey and find that highly related groups of prey with a semelparous reproductive strategy are the most likely to evolve gregarious foraging behaviour mediated by the benefit of vigilance. These findings, combined with earlier studies with evolving digital organisms, further sharpen our understanding of the factors favouring grouping behaviour.


Production and characterization of monoclonal antibody specific for NS3 helicase of hepatitis C virus.
Hepatitis C virus (HCV) infection is the major etiological agent of chronic hepatitis, which leads to liver cirrhosis and hepatocellular carcinomas. HCV NS3 helicase is a promising target of anti-virus therapy. In this report, we discuss a strategy to generate monoclonal antibodies (MAbs) of the HCV NS3 helicase, and investigate its potential characteristic. Our results showed the production of MAbs against NS3 helicase, which could specifically recognize the native NS3 helicase in transiently transfected cells in the immunofluorescence experiment. The resultant MAbs were used as the first antibody in Western blot analyses, and observed the specific band that defines the NS3 helicase. Likewise, one MAb could inhibit the NS3 helicase enzymatic activity distinctly in the NS3 helicase-mediated DNA-unwinding assay. To conclude, these antibodies may be useful to generate specific diagnostic tools for HCV infection and may also be developed for potential therapeutics.


Impaired GABAergic transmission disrupts normal homeostatic plasticity in rat cortical networks.
In the cortex, homeostatic plasticity appears to be a key process for maintaining neuronal network activity in a functional range. This phenomenon depends on close interactions between excitatory and inhibitory circuits. We previously showed that application of a high frequency of stimulation (HFS) protocol in layer 2/3 induces parallel potentiation of excitatory and inhibitory inputs on layer 5 pyramidal neurons, leading to an unchanged excitation/inhibition (E/I) balance. These coordinated long-term potentiations of excitation and inhibition correspond to homeostatic plasticity of the neuronal networks. We showed here, on the rat visual cortex, that blockade (with gabazine) or overactivation (with 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) of GABA(A) receptors enhanced the E/I balance and prevented the potentiation of excitatory and inhibitory inputs after an HFS protocol. These impairements of the GABAergic transmission led to a long-term depression-like effect after an HFS protocol. We also observed that the blockade of inhibition reduced excitation (by 60%), and conversely, the blockade of excitation decreased inhibition (by 90%). These results support the idea that inhibitory interneurons are critical for recurrent interactions underlying homeostatic plasticity in cortical networks.


[Palliative surgical treatment of spastic paralysis in the lower extremity].
The purpose of this paper is to describe our experience with and to review the best results in the surgical treatment of patients suffering from spastic paralysis of the lower limbs. To enable a correct indication of the techniques to be employed the authors recommend a thorough examination of the types of deformity (fixed, dynamic or mixed) and the use of specific tests for exploring the different deformities. These are necessary steps to be able to interpret the different disorders in a global manner and thus reach diagnostics that provide us with a proper surgical therapeutic orientation about the spastic hip, knee, ankle and foot. Due to the importance of the overall problem, it is becoming increasingly more frequent to advise multidisciplinary work involving the collaboration of different specialists (neurologists, rehabilitators, physiotherapists, psychologists, paediatricians, neurophysiologists and orthopaedic surgeons). Spasticity is as heterogeneous as the results of the different treatment projects. The techniques used must allow the rehabilitation therapy to be continued. Surgical intervention is recommended when the damage to the CNS has stabilised and the patient is over 4 years old. The psychic state of the patient and the family must also be evaluated. The objective of the treatment in patients who can walk is to improve motor functioning, the type of gait and to prevent fixed deformities from developing. In patients who do not walk, the aim is to improve their hygiene and their capacity to sit and to walk. These indications are indispensable to be able to successfully perform a little-known area of orthopaedic surgery which does not respond to the techniques used in flaccid paralysis surgery.


Desmoplastic fibroblastoma of the left upper arm.
An elderly female patient presented to the clinic with a several-week history of a mass in her left upper arm that was tender to the touch. The mass was initially thought to be a schwannoma of the left radial nerve based on imaging and was surgically removed. The pathology report revealed an uncommon diagnosis of desmoplastic fibroblastoma.


[Swine plague: symptoms, epizootiology and diagnosis].
The clinical signs, laboratory diagnosis and modes of transmission of classical swine fever are described. Special attention is paid to combinations of signs of disease which should arise suspicion to the veterinary practitioner in the present epizootic.


Drosophila melanogaster grooming possesses syntax with distinct rules at different temporal scales.
Mathematical modeling of behavioral sequences yields insight into the rules and mechanisms underlying sequence generation. Grooming in Drosophila melanogaster is characterized by repeated execution of distinct, stereotyped actions in variable order. Experiments demonstrate that, following stimulation by an irritant, grooming progresses gradually from an early phase dominated by anterior cleaning to a later phase with increased walking and posterior cleaning. We also observe that, at an intermediate temporal scale, there is a strong relationship between the amount of time spent performing body-directed grooming actions and leg-directed actions. We then develop a series of data-driven Markov models that isolate and identify the behavioral features governing transitions between individual grooming bouts. We identify action order as the primary driver of probabilistic, but non-random, syntax structure, as has previously been identified. Subsequent models incorporate grooming bout duration, which also contributes significantly to sequence structure. Our results show that, surprisingly, the syntactic rules underlying probabilistic grooming transitions possess action duration-dependent structure, suggesting that sensory input-independent mechanisms guide grooming behavior at short time scales. Finally, the inclusion of a simple rule that modifies grooming transition probabilities over time yields a generative model that recapitulates the key features of observed grooming sequences at several time scales. These discoveries suggest that sensory input guides action selection by modulating internally generated dynamics. Additionally, the discovery of these principles governing grooming in D. melanogaster demonstrates the utility of incorporating temporal information when characterizing the syntax of behavioral sequences.


Effects of prostaglandin E1 on lipolysis and plasma free fatty acids in the fasted rat.
Contrary to published reports, prostaglandin E(1) (PGE(1)) in vitro and in vivo inhibited fasting lipolysis in rats. Adipose tissue lipolysis was inhibited when the tissue was incubated in the presence of PGE(1) and when the compound was administered intravenously. A biphasic plasma free fatty acid (FFA) response was obtained in fasted rats after intravenous injection of 80 micrograms of PGE(1) per kg body weight; plasma FFA concentrations were lowered at 7 min, elevated at 15 min, and at normal concentrations at 30 min. The FFA depression at 7 min was independent of the animal's nutritional state, but the rebound at 15 min did not occur in fed rats. The plasma FFA rebound in fasted rats at 15 min may be a consequence of rapid inactivation of PGE(1), followed by unopposed activity of factors which enhance fasting lipolysis.


Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients.
Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1(+)) and HIV-2(+) individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2(+) patients, despite the reduced viremia (undetectable to 2.6 × 10(4) RNA copies/ml). However, tat mRNA transcripts were observed at significantly lower levels in HIV-2(+) patients, suggesting that the rate of de novo infection is decreased in these patients. Our data also reveal a direct relationship of gag and tat transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2(+) patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2(+) patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection.


C-C Bond Formation of Mg- and Zn-Activated Carbon Dioxide.
Gas-phase activation of CO2 by chloride tagged metal atoms, [ClM]- (M=Mg, Zn), has been investigated by mass spectrometry and high-level quantum chemistry. Both metals activate CO2 with significant bending of the CO2 moiety to form complexes with the general formula [ClM,CO2 ]- . The structure of the metal-CO2 complex depends on the method of formation, and the energy landscapes and reaction dynamics have been probed by collisional induced dissociation and thermal ion molecule reactions with isotopically labeled species. Having established these structural relationships, the gas-phase reactivity of [ClM(κ2 -O2 C)]- with acetaldehyde (here considered a carbohydrate mimic) was then studied. Formation of lactate and enolate-pyruvate complexes are observed, showing that CO2 fixation by C-C bond formation takes place. For M=Zn, even formation of free pyruvate ([C3 H3 O3 ]- ) is observed. Implications of the observed CO2 reactivity for the electrochemical conversion of carbon dioxide, and to biochemical and artificial photosynthesis is briefly discussed. Detailed potential energy diagrams obtained by the quantum chemical calculations offer models consistent with experimental observation.


Neural correlates of decisions.
Once considered the province of philosophy and the behavioral sciences, the process of making decisions has received increasing scrutiny from neurobiologists. Recent research suggests that sensory judgements unfold through the gradual accumulation of neuronal signals in sensory-motor pathways, favoring one alternative over others. Stored representations of the outcome of prior actions activate neurons in many of these same areas during decision-making. The challenge for neurobiologists lies in deciphering how signals from these disparate areas are integrated to form a single behavioral choice and the mechanisms responsible for selecting the appropriate information upon which decisions should be informed in particular contexts.


The structure of a 15-stranded actin-like filament from Clostridium botulinum.
Microfilaments (actin) and microtubules represent the extremes in eukaryotic cytoskeleton cross-sectional dimensions, raising the question of whether filament architectures are limited by protein fold. Here, we report the cryoelectron microscopy structure of a complex filament formed from 15 protofilaments of an actin-like protein. This actin-like ParM is encoded on the large pCBH Clostridium botulinum plasmid. In cross-section, the ~26 nm diameter filament comprises a central helical protofilament surrounded by intermediate and outer layers of six and eight twisted protofilaments, respectively. Alternating polarity of the layers allows for similar lateral contacts between each layer. This filament design is stiffer than the actin filament, and has likely been selected for during evolution to move large cargos. The comparable sizes of microtubule and pCBH ParM filaments indicate that larger filament architectures are not limited by the protomer fold. Instead, function appears to have been the evolutionary driving force to produce broad, complex filaments.


Progressive aortic dilation and aortic stiffness in children with repaired tetralogy of Fallot.
Progressive aortic dilation occurs in patients with tetralogy of Fallot (TOF), possibly due to abnormal histopathology of the aortic media that weakens the aortic wall. This medial histopathology may be reflected as aortic stiffness, which in turn may predict progressive aortic dilation. To test this theory, we studied the relationship between aortic wall stiffness, measured by pulse wave velocity (PWV), and subsequent aortic dilation in 32 consecutive patients with repaired TOF. The ascending aortic diameter (AOD) was obtained by two-dimensional transthoracic echocardiography performed at baseline and at the follow-up examination, 7.6 ± 2.0 years after baseline. TOF patients exhibited significantly greater AODs than normal reference values, at baseline (19.8 ± 5.0 vs 14.3 ± 3.1 mm; P = 0.0001) and at the follow-up examination (25.9 ± 3.8 vs 18.1 ± 2.4 mm; P = 0.0001). The observed change in AOD during the follow-up period (0.83 ± 0.43 mm/year) was significantly larger than the change that would be expected by the patient's growth (0.50 ± 0.25 mm/year; P = 0.0001). The PWV at baseline correlated positively with both AOD at follow-up (P = 0.0018) and the annual rate of aortic dilation (P = 0.0007). On multivariate regression analysis, PWV remained a significant and independent predictor of subsequent aortic dilation. These results suggest a causative role for aortic stiffening in the progressive aortic dilation noted in TOF, indicating that incorporating aortic stiffness as well as aortic diameter in the assessment of TOF aortopathy may help better define the need for, and the timing of, medical intervention.


Advances in paediatric dentistry.
The problems facing paediatric dentists have not changed over the years, management of caries and orodental trauma still takes up the greatest proportion of their time. What has changed are the treatments available and in this paper some of the more interesting recent developments in this field are summarised.


Barosmin against postprandial hyperglycemia: outputs from computational prediction to functional responses in vitro.
Previously, barosmin has been demonstrated to possess anti-diabetic action. However, its effect to inhibit α-amylase and α-glucosidase, including glucose utilization efficacy, has yet to be revealed. Hence, the current study attempted to assess the efficiency of barosmin in inhibiting the α-amylase, α -glucosidase, and dipeptidyl peptidase 4 enzymes, including glucose uptake efficacy. Molecular docking and simulation were performed using AutoDock Vina and Gromacs respectively followed by gene ontology analysis using the database for annotation, visualization, and integrated discovery. Further, in vitro enzyme inhibitory activities and glucose uptake assay were performed in L6 cell lines. Density functional theory analysis detailed mechanistic insights into the crucial interaction sites of barosmin of which the electron-dense region was prone to nucleophilic attack (O-atoms) whereas hydroxyl groups (-OH) showed affinity for electrophilic attacks. Barosmin showed good binding affinity with α-amylase (-9.2 kcal/mol), α-glucosidase (-10.7 kcal/mol), and dipeptidyl peptidase 4 (-10.0 kcal/mol). Barosmin formed stable nonbonded contacts with active site residues of aforementioned enzymes throughout 200 ns molecular dynamics simulation. Further, it regulated pathway concerned with glucose homeostasis i.e. tumor necrosis factor signaling pathway. In addition, barosmin showed α-amylase (IC50= 95.77 ± 23.33 µg/mL), α-glucosidase (IC50= 68.13 ± 2.95 µg/mL), and dipeptidyl peptidase 4 (IC50= 13.27 ± 1.99 µg/mL) inhibitory activities including glucose uptake efficacy in L6 cell lines (EC50= 12.46 ± 0.90 µg/mL) in the presence of insulin. This study presents the efficacy of the barosmin to inhibit α-amylase and α-glucosidase and glucose uptake efficacy in L6 cell lines via the use of multiple system biology tools and in vitro techniques.Communicated by Ramaswamy H. Sarma.


Newly graduated nurses' occupational commitment and its associations with professional competence and work-related factors.
To explore newly graduated nurses' occupational commitment and its associations with their self-assessed professional competence and other work-related factors. As a factor affecting nurse turnover, newly graduated nurses' occupational commitment and its associations with work-related factors needs exploring to retain adequate workforce. Nurses' commitment has mainly been studied as organisational commitment, but newly graduated nurses' occupational commitment and its association with work-related factors needs further studying. This study used descriptive, cross-sectional, correlation design. A convenience sample of 318 newly graduated nurses in Finland participated responding to an electronic questionnaire. Statistical software, NCSS version 9, was used in data analysis. Frequencies, percentages, ranges, means and standard deviations summarised the data. Multivariate Analyses of Variance estimated associations between occupational commitment and work-related variables. IBM SPSS Amos version 22 estimated the model fit of Occupational Commitment Scale and Nurse Competence Scale. Newly graduated nurses' occupational commitment was good, affective commitment reaching the highest mean score. There was a significant difference between the nurse groups in favour of nurses at higher competence levels in all subscales except in limited alternatives occupational commitment. Multivariate analyses revealed significant associations between subscales of commitment and competence, turnover intentions, job satisfaction, earlier professional education and work sector, competence counting only through affective dimension. The association between occupational commitment and low turnover intentions and satisfaction with nursing occupation was strong. Higher general competence indicated higher overall occupational commitment. Managers' recognition of the influence of all dimensions of occupational commitment in newly graduated nurses' professional development is important. Follow-up studies of newly graduated nurses' commitment, its relationship with quality care, managers' role in enhancing commitment and evaluation of the impact of interventions on improving commitment need further studying.


Emerging insights into the genetic basis of canine hip dysplasia.
Canine hip dysplasia (CHD) is the most common inherited polygenic orthopedic trait in dogs with the phenotype influenced also by environmental factors. This trait was described in the dog in 1935 and leads to a debilitating secondary hip osteoarthritis. The diagnosis is confirmed radiographically by evaluating signs of degenerative joint disease, incongruence, and/or passive hip joint laxity. There is no ideal medical or surgical treatment so prevention based on controlled breeding is the optimal approach. The definitive CHD diagnosis based on radiographic examination involves the exposure to ionizing radiation under general anesthesia or heavy sedation but the image does not reveal the underlying genetic quality of the dog. Phenotypic expression of CHD is modified by environmental factors and dogs with a normal phenotype can be carriers of some mutations and transmit these genes to their offspring. Programs based on selection of dogs with better individual phenotypes for breeding are effective when strictly applied but remain inferior to the selection of dogs based on estimation of breeding values. Molecular studies for dissecting the genetic basis of CHD are ongoing, but progress has been slow. In the future, the recommended method to improve hip quality in controlled breeding schemes, which will allow higher selection pressure, would be based on the estimation of the genomic breeding value. Since 2012, a commercial DNA test has been available for Labrador Retrievers using a blood sample and provides a probability for development of CHD but we await evidence that this test reduces the incidence or severity of CHD.


Pre-Whitnall levator recession with hang-back sutures in Graves orbitopathy.
To describe a technique for lengthening the levator palpebrae muscle at the level of the transverse orbital ligament (Whitnall ligament) by using hang-back sutures in cases of upper eyelid retraction in Graves orbitopathy, and to report its results. A cohort of consecutive patients undergoing this procedure by a single surgeon was analyzed. The surgical technique involved division of the levator muscle high up, at the level of the transverse orbital ligament, with lengthening of the muscle by a graded amount with the use of nonabsorbable hang-back sutures. The length of the sutures was twice the amount of desired lowering of the eyelid. Surgery was performed on 38 eyelids of 21 patients. The mean preoperative eyelid retraction was 4.7 mm (range, 3 mm to 8 mm). Thirty-two eyelids (84%) were within 1 mm of the desired postoperative position. One patient required reoperation for significant undercorrection (2 eyelids), another 4 had ptosis repairs for overcorrection (5 eyelids, one of which was only 1-mm overcorrected). One eyelid required medial contour repair, but none needed lateral contour correction. This procedure gives a relatively predictable result in patients with moderate to severe upper eyelid retraction and avoids the postoperative complication of contour deformities, especially lateral flare.


Structure, dipole moment and large amplitude motions of 1-benzofuran.
The rotational spectrum of 1-benzofuran has been investigated by three different rotational spectroscopy techniques: (i) millimeterwave absorption free jet spectroscopy, useful for a fast assignment of the spectrum; (ii) molecular beam Fourier transform microwave spectroscopy, sensitive to detect less abundant isotopic species in natural abundance; (iii) waveguide conventional microwave spectroscopy, useful for the study of intramolecular dynamics, through the rotational spectra of the vibrational satellites of low energy modes. Besides the rotational spectrum of the ground state of the normal species, the spectra of 9 singly substituted 13C and 18O isotopomers in natural abundance, and of 6 vibrational satellites, have been measured. Precise structural parameters for the molecule, as well as information on the potential energy surface of the low energy vibrations, have been obtained. The dipole moment components have been determined to be micro(a)= 0.216 (2) and micro(b)= 0.720 (3) D, respectively.


Experiential learning in physical therapy education.
Experiential learning can provide students in entry-level physical therapy (PT) education programs the opportunity to practice skills and techniques, learned in the classroom, in a real-world setting. Experiential learning is currently being utilized in all entry-level PT programs in the form of professional practice experiences but may be integrated throughout the curriculum to enhance student engagement and knowledge application and retention. The purpose of this paper is to express the need for increased integration of experiential learning into entry-level PT education curricula. Experiential learning can effectively replace a portion of in-class laboratory time in entry-level PT education programs. Several methods of experiential learning exist, including simulation, integrated clinical experiences, service learning, community patient resource groups, and professional practice opportunities. Students benefit from the ability to practice hands-on skills in a safe, nonjudgmental environment. Students can still experience consequences of poor decisions but can have multiple opportunities to master the skill without the fear of negative outcomes. Incorporation of high-risk age ranges and diagnoses can be achieved through simulation. Experiential learning can be integrated into any PT curriculum if faculties are committed and flexible. Experiential learning may be particularly useful in specialty practice areas where there are fewer opportunities for students to practice skills. The practice of reflection upon experiences that is commonly performed in conjunction with experiential learning will help prepare students for the type of reflective practice that is essential to transition from novice to expert practitioners.


Stereospecific intramolecular C-H amination of 1-aza-2-azoniaallene salts.
We report that 1-aza-2-azoniaallene salts, generated from α-chloroazo compounds by treatment with halophilic Lewis acids, participate in intramolecular C-H amination reactions to provide pyrazoline products in good to excellent yield. This intramolecular amination occurs readily at both benzylic and tertiary aliphatic positions and proceeds at an enantioenriched chiral center without loss of enantiomeric excess. A competition reaction shows that insertion occurs more readily at an electron-rich benzylic position than an electron-deficient one. These observations are consistent with the 1-aza-2-azoniaallene intermediate reacting as a nitrenium-like ion by a concerted insertion mechanism.


Laser-heated emissive plasma probe.
Emissive probes are standard tools in laboratory plasmas for the direct determination of the plasma potential. Usually they consist of a loop of refractory wire heated by an electric current until sufficient electron emission. Recently emissive probes were used also for measuring the radial fluctuation-induced particle flux and other essential parameters of edge turbulence in magnetized toroidal hot plasmas [R. Schrittwieser et al., Plasma Phys. Controlled Fusion 50, 055004 (2008)]. We have developed and investigated various types of emissive probes, which were heated by a focused infrared laser beam. Such a probe has several advantages: higher probe temperature without evaporation or melting and thus higher emissivity and longer lifetime, no deformation of the probe in a magnetic field, no potential drop along the probe wire, and faster time response. The probes are heated by an infrared diode laser with 808 nm wavelength and an output power up to 50 W. One probe was mounted together with the lens system on a radially movable probe shaft, and radial profiles of the plasma potential and of its oscillations were measured in a linear helicon discharge.


Cortical granule exocytosis in C. elegans is regulated by cell cycle components including separase.
In many organisms, cortical granules undergo exocytosis following fertilization, releasing cargo proteins that modify the extracellular covering of the zygote. We identified cortical granules in Caenorhabditis elegans and have found that degranulation occurs in a wave that initiates in the vicinity of the meiotic spindle during anaphase I. Previous studies identified genes that confer an embryonic osmotic sensitivity phenotype, thought to result from abnormal eggshell formation. Many of these genes are components of the cell cycle machinery. When we suppressed expression of several of these genes by RNAi, we observed that cortical granule trafficking was disrupted and the eggshell did not form properly. We conclude that osmotic sensitivity phenotypes occur because of defects in trafficking of cortical granules and the subsequent formation of an impermeable eggshell. We identified separase as a key cell cycle component that is required for degranulation. Separase localized to cortically located filamentous structures in prometaphase I upon oocyte maturation. After fertilization, separase disappeared from these structures and appeared on cortical granules by anaphase I. RNAi of sep-1 inhibited degranulation in addition to causing extensive chromosomal segregation failures. Although the temperature-sensitive sep-1(e2406) allele exhibited similar inhibition of degranulation, it had minimal effects on chromosome segregation. These observations lead us to speculate that SEP-1 has two separable yet coordinated functions: to regulate cortical granule exocytosis and to mediate chromosome separation.


Cardiometabolic Effects of Endocrine Treatment of Estrogen Receptor-Positive Early Breast Cancer.
Estrogen receptor-positive early breast cancer is common and has a relatively good prognosis. It shares risk factors with cardiovascular disease, and cardiovascular disease is an important competing cause of mortality. Adjuvant endocrine therapy with aromatase inhibitors (requiring concomitant ovarian suppression in premenopausal women) or selective estrogen receptor modulators (usually tamoxifen) exert oncologic benefits by respectively inhibiting estradiol synthesis or breast estrogen receptor signaling. Aromatase inhibitors cause systemic estradiol depletion. Tamoxifen has mixed agonistic/antagonistic effects in a tissue-dependent fashion. Given that estrogens modulate cardiometabolic risk, a review of the effects of endocrine therapy on cardiometabolic outcomes is pertinent. The current, but limited, evidence suggests that tamoxifen treatment, although associated with increases in body fat, hepatic steatosis, serum triglycerides, and diabetes risk, modestly reduces low-density lipoprotein cholesterol and lipoprotein(a) and may have favorable effects on markers of subclinical atherosclerosis. Tamoxifen is associated with either no effect on, or a reduction in, cardiovascular events, and it is associated with an increase in venous thromboembolic events. Aromatase inhibitors, although fewer studies are available and often confounded by comparison with tamoxifen, have not been consistently associated with adverse changes in cardiometabolic risk factors or increases in cardiovascular events. Further clinical trials designed to evaluate cardiometabolic outcomes are needed to more accurately determine the effects of endocrine therapy on cardiovascular risks, to inform individualized decisions regarding choice and duration of endocrine therapy, and to implement evidence-based strategies to mitigate cardiometabolic risks. In the meantime, although breast cancer-specific evidence for benefit of lifestyle measures is available and recommended routinely, proactive monitoring and treatment of cardiovascular risk factors should follow general population recommendations.


Structure, organization, and chromosomal mapping of the human neurogranin gene (NRGN).
In this report the identification, structure, and chromosomal localization of the human neurogranin gene (NRGN) are described. NRGN is the human homolog of the rat Ng/RC3 gene, which encodes a brain-specific protein expressed in telencephalic neurons. The human NRGN gene spans approximately 12 kb and contains four exons and three introns. All splice acceptor and donor sites conform to the canonical AG/GT rule. Human neurogranin sequence predicts a 78-amino-acid protein with 5 amino acids encoded by exon 1 and the remaining 73 amino acids encoded by exon 2. The third and fourth exons contain untranslated sequences. The overall degree of homology between the human and the rat coding sequences is 90% for the nucleic acid sequence, with 96% identity and 97.5% similarity at the protein level. The NRGN gene is expressed exclusively in brain as a single 1.3-kb mature mRNA. The promoter lacks both TATA and CAAT boxes, but shows a consensus sequence for an initiator element located 234 bases upstream from the AUG initiation codon. The 5'-flanking region contains multiple putative binding sites for transcription factors such as Sp1, GCF, AP2, and PEA3. Analysis of a panel of radiation hybrids has led to localization of the NRGN gene in YAC 763A2 (CEPH), previously mapped at 11q24. This locus is contained in a region of conserved synteny with mouse chromosome 9.


Selective labeling of the inner liposome leaflet by fluorescent lipid probes, and studies of liposome fusion with influenza virus.
The inner leaflet of unilamellar lipid vesicles was labeled with fluorescent lysophosphatidylcholines. The probes make a donor-acceptor pair in resonance energy transfer (RET), being labeled with 9-anthrylvinyl (L-APC, donor) and 3-perylenoyl (L-PPC, acceptor) fluorophores. They migrate rapidly between bilayers through the water phase: tau 1/2 of equilibration is approximately 5 min at 37 degrees C. The probe(s) can be removed from the outer leaflet of uniformly labeled medium-size unilamellar vesicles (MUV) by repeated washings with excess unlabeled large unilamellar vesicles (LUV) (separation by centrifugation). The probes flip-flop across bilayers rather slowly. MUV containing the ganglioside GT1b and labeled with the L-APC/L-PPC pair in the inner leaflet were fused with an equal amount of influenza virus; the process was monitored by an increase of the donor fluorescence in RET assay. If inner MUV leaflet was labeled with the anthrylvinyl probe only, the probe fluorescence decreased by half when the probe was removed from the outer leaflets of the fused membranes. This shows that the lipids of the inner and outer leaflets of the MUV randomize in the process of fusion.


Regional filter heparinization for continuous veno-venous hemofiltration in liver transplant recipients.
To study safety, clinical and operative feasibility of continuous veno-venous hemofiltration (CVVH) with anticoagulation only of the filter in patients at risk for bleeding. This prospective, comparative, non randomised study was completed at an intensive care unit of a teaching NHS hospital. Sixteen liver transplant (LT) recipients with acute renal failure needing CVVH were treated with a regional anticoagulation protocol (heparin and protamine were administered respectively pre- and post-filter) and compared to 11 critically ill subjects who received a standard low-heparin treatment. Activated coagulation time (ACT) monitoring was used to adjust anticoagulation and heparin neutralization. Mean circuit life was 35.8+/-13.6 hours (95% CI 28.5-43.1) in patients receiving regional anticoagulation and 34.4+/-14 hours in controls (95% CI 25.5-43.3; p=0.7). Fourty-eight circuits (47.5% of the total) in the heparin-protamine group had a life-span longer than 30 hours and other 22 (21.7%) were changed intentionally after 24 hours of use in absence of clots. None of the patients in both the studied groups had bleeding or hemodynamic complications and their azotemic control was always satisfactory. In LT recipients, regional anticoagulation can achieve a circuits life-span comparable to that from systemic anticoagulation with satisfactory safety and simplicity of use.


Cholesterol induces fetal rat enterocyte death in culture.
The effect of cholesterol on fetal rat enterocytes and IEC-6 cells (line originated from normal rat small intestine) was examined. Both cells were cultured in the presence of 20 to 80 microM cholesterol for up to 72 h. Apoptosis was determined by flow cytometric analysis and fluorescence microscopy. The expression of HMG-CoA reductase and peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by RT-PCR. The addition of 20 microM cholesterol reduced enterocyte proliferation as early as 6 h of culture. Reduction of enterocyte proliferation by 28 and 41% was observed after 24 h of culture in the presence and absence of 10% fetal calf serum, respectively, with the effect lasting up to 72 h. Treatment of IEC-6 cells with cholesterol for 24 h raised the proportion of cells with fragmented DNA by 9.7% at 40 microM and by 20.8% at 80 microM. When the culture period was extended to 48 h, the effect of cholesterol was still more pronounced, with the percent of cells with fragmented DNA reaching 53.5% for 40 microM and 84.3% for 80 microM. Chromatin condensation of IEC-6 cells was observed after treatment with cholesterol even at 20 microM. Cholesterol did not affect HMG-CoA reductase expression. A dose-dependent increase in PPARgamma expression in fetal rat enterocytes was observed. The expression of PPAR-gamma was raised by 7- and 40-fold, in the presence and absence of fetal calf serum, respectively, with cholesterol at 80 mM. The apoptotic effect of cholesterol on enterocytes was possibly due to an increase in PPARgamma expression.


Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.
We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1-15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [-0.6 +/- 2.2 sd (n = 10) vs. -0.6 +/- 1.4 sd (n = 21); P = 0.95], childhood height [-2.6 +/- 1.1 sd (n = 14) vs. -2.1 +/- 1.6 sd (n = 23); P = 0.28], or target height [-0.4 +/- 0.9 sd (n = 14) vs. -0.2 +/- 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.


The relation between uric acid level and blood pressure values among patients hospitalized in a department of internal medicine.
The relationship between uric acid (UA) level and blood pressure (BP) is not clear, although most studies suggest BP reduction in patients treated with UA level lowering agents. The aim of the study was to evaluate the relationship between UA level and BP among patients hospitalized in a department of internal medicine. We also intended to investigate the relation between the allopurinol dose prescribed and BP. We reviewed hospital records of 561 patients (mean age: 65.46 ±17.46 years) hospitalized in a department of internal medicine, in whom UA level was determined on admission. We did not find a significant correlation between UA level and BP values in the whole group, nor in patients not taking any BP-lowering or any UA-lowering drug. Multivariable analysis showed that allopurinol dose was not independently related to BP. Age (OR = 1.04, 95% CI: 1.03-1.06 per 1 year), diabetes (OR = 1.90, 95% CI: 1.14-3.16), stage 2 (OR = 4.96, 95% CI: 2.15-11.46) and stage 3 obesity (OR = 13.66, 95% CI: 5.90-31.60), both vs. patients without stage 2/3 obesity, but not UA level, were independently related to the diagnosis of hypertension. Our study does not confirm an independent relationship between UA level and BP nor between UA lowering and BP in a population of hospitalized patients.


Changing patterns of drug-resistant Shigella isolates in egypt.
The emergence of multidrug resistance (MDR) is a serious problem in treating shigellosis. There are limited existing data examining the change in the antimicrobial resistance profile of Shigella in Egypt. We previously reported that 58% of the Shigella isolates in Egypt were resistant to at least one member of the three different antimicrobial groups. This study was performed to determine the antimicrobial resistance profile of Shigella, determine their possible mechanisms of resistance, and compare their resistance profile to those reported 20 years ago. Stool samples were collected from 500 subjects and processed for the isolation and identification of Shigella. The susceptibility of the isolates to 11 different antimicrobials was determined using the disc diffusion method. Of 500 stool cultures, 24 (4.8%) samples were positive for Shigella. There was a high percentage of resistance to ampicillin (88%), tetracycline (83%), and sulfamethoxazole-trimethoprim (75%). Also, there was a moderate percentage of resistance to chloramphenicol (46%), streptomycin (42%), ceftazidime (33%), and cefotaxime (25%). A lower percentage of resistance was recorded for amikacin, nalidixic acid (17% each), and ofloxacin (7%), while no resistance was found to ciprofloxacin (0%). Twenty-one of the isolates (88%) were resistant to at least three different antimicrobial groups (indicating MDR). The average number of antimicrobial agents to which the Shigella isolates were resistant was 4.3±1.4, while it was 3.4±1.5 in the same locality in 1994. These data demonstrate that there is a marked increase in MDR and change in the resistance patterns of Shigella over the past 20 years.


Effect of blood transfusion on gene expression of transforming growth factor beta-1 and the alpha subunit of interleukin-2 receptor in a model of colonic wound healing.
Blood transfusions have been shown in the past to compromise wound healing in experimental models of colonic anastomosis. Transforming growth factor beta (TGFbeta) has been proposed to play a major role in the process of colonic wound healing, and its expression is believed to be modulated by interleukin-2 (IL2). According to an earlier report, the postoperative administration of the histamine receptor-2 antagonist ranitidine increases the blood levels of soluble IL2 receptor in humans undergoing abdominal surgery and could thus affect molecular determinants of colonic anastomosis. In this study we examined the effect of blood transfusions, with and without ranitidine administration, on the gene expression of TGFbeta(1) and the specificity-conveying alpha subunit of the receptor for IL2, in rat perianastomotic tissue. Analysis of gene expression by semiquantitative RT-PCR revealed a tendency for downregulation of both genes, albeit in a statistically nonsignificant manner. This effect was not prevented by the postoperative administration of ranitidine. On the other hand, there appears to be a significant correlation between expression of TGFbeta(1) and that of IL2 receptor alpha subunit, irrespective of treatment.


[German Translation and Validation of the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's disease (SEND-PD)].
The aim of the present study was to validate and provide a German version of the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's disease (SEND-PD) of Martínez-Martín et al. (2012). The German version of the SEND-PD was evaluated in a sample consisting of 96 patients with Parkinson's disease (PD) (mean age: 65.3 years ± 9.6, 29 female). This scale includes 12 items, representing the domains psychotic symptoms, mood/apathy and impulse control disorders. Reliability and validity analyses were conducted. The examined patients presented a few neuropsychiatric symptoms. Explorative factor analyses identified the proposed three dimensions solution. The items of the mood/apathy domain were homogenous and selective, and the domain showed acceptable internal consistency. For the other two domains, the values were only partially acceptable. Convergent, discriminate and construct validity were shown. The German version of the SEND-PD is sufficiently reliable and valid to be adopted in German speaking countries. However, since patients showed only a few symptoms in the dimensions of psychotic symptoms and impulse control disorders, these two domains can be evaluated only to a limited extent.


[Collisional energy transfer of the Rb (7 2D) state by ground state K atoms].
In the K-Rb vaper mixtures, the two-photon stepwise excitation of rubidium atoms from the ground state to the state Rb 7 2D is obtained by the use of a rubidium lamp and a cw dye laser. The cross sections for the collisional process Rb (7 2D) +K (4S) -->Rb (5S) +K (7S. 5D) have been measured by observation of the resulting fluorescence. The ratio of K (7S. 5D) to Rb7D fluorescence contains a contribution from K 7S<==>5D mixing. The contribution could effectively be subtracted out using a second experiment in which a potassium lamp and a cw dye laser were used to pump the K7S or 5D state, and the ratio of 7S to 5D or 5D to 7S fluorescence was monitored. The cross sections (in 10(-15)cm2) for Rb7D-->K7S. 5D excitation transfer are 25.8 +/- 10. 3 and 1.5 +/- 0.6 respectively.


Methotrexate with citrovorum factor in low-risk gestational trophoblastic tumor.
From January 1976 through December 1985, methotrexate (MTX) with citrovorum factor (CF) was administered as primary treatment to 57 patients with low-risk gestational trophoblastic tumor (GTT); 51 patients were non-metastatic and 6 were metastatic GTT. The median number of courses needed to achieve biochemical remission was two (range, 1-7). Complete remission was attained in 95% of non-metastatic GTT patients with postmolar persistent trophoblastic disease, but when choriocarcinoma was histologically confirmed, this fell to 60%. The cure rate of metastatic GTT patients was only 50%. The overall remission rate with the MTX-CF combination was 84.2%. Toxicity was mild, consisting of myelosuppression and mucositis. Fifteen patients were resistant to MTX-CF, or relapsed subsequently, but they all achieved remission with chemotherapy rescue treatment (VP 16 alone, EMA/CO, CHAMOCA). Two patients required a pulmonary lobectomy. They are all still alive in biochemical remission with a median survival of 54 months. Our experience suggests that drug resistance and relapse rate seem related to a beta-HCG value higher than 10(4), an enlarged uterus with myometrial deep involvement, and a histologically confirmed diagnosis of choriocarcinoma. In conclusion, the MTX-CF combination is effective in postmolar GTT, whereas a different therapeutic approach may be considered for a "special" low-risk group of patients, on the basis of prognostic factors.


Progress in finding pathogenic DNA copy number variations in dyslipidemia.
DNA copy number variations (CNVs) are large-scale mutations that include deletions and duplications larger than 50 bp in size. In the era when single-nucleotide variations were the major focus of genetic technology and research, CNVs were largely overlooked. However, CNVs clearly underlie a substantial proportion of clinical disorders. Here, we update recent progress in identifying CNVs in dyslipidemias. Until last year, only the LDLR and LPA genes were appreciated as loci within which clinically relevant CNVs contributed to familial hypercholesterolemia and variation in Lp(a) levels, respectively. Since 2017, next-generation sequencing panels have identified pathogenic CNVs in at least five more genes underlying dyslipidemias, including a PCSK9 whole-gene duplication in familial hypercholesterolemia; LPL, GPIHBP1, and APOC2 deletions in hypertriglyceridemia; and ABCA1 deletions in hypoalphalipoproteinemia. CNVs are an important class of mutation that contribute to the molecular genetic heterogeneity underlying dyslipidemias. Clinical applications of next-generation sequencing technologies need to consider CNVs concurrently with familiar small-scale genetic variation, given the likely implications for improved diagnosis and treatment.


Impaired In Vivo Gamma Oscillations in the Medial Entorhinal Cortex of Knock-in Alzheimer Model.
The entorhinal cortex (EC) has bidirectional connections with the hippocampus and plays a critical role in memory formation and retrieval. EC is one of the most vulnerable regions in the brain in early stages of Alzheimer's disease (AD), a neurodegenerative disease with progressive memory impairments. Accumulating evidence from healthy behaving animals indicates gamma oscillations (30-100 Hz) as critical for mediating interactions in the circuit between EC and hippocampus. However, it is still unclear whether gamma oscillations have causal relationship with memory impairment in AD. Here we provide the first evidence that in vivo gamma oscillations in the EC are impaired in an AD mouse model. Cross-frequency coupling of gamma (30-100 Hz) oscillations to theta oscillations was reduced in the medial EC of anesthetized amyloid precursor protein knock-in (APP-KI) mice. Phase locking of spiking activity of layer II/III pyramidal cells to the gamma oscillations was significantly impaired. These data indicate that the neural circuit activities organized by gamma oscillations were disrupted in the medial EC of AD mouse model, and point to gamma oscillations as one of possible mechanisms for cognitive dysfunction in AD patients.


A MicroRNA Signature in Acute Coronary Syndrome Patients and Modulation by Colchicine.
Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS. A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium. Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA. The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy.


Remote morphological changes in the white matter after ischaemic stroke.
Acute phase of stroke is the focus of most experimental and clinical studies on cerebral ischaemia. The scarcity of data on remote changes led us to examine the morphological pictures of brains after ischaemic insults. We paid special attention to the white matter capillaries. We microscopically evaluated 10 brains of patients who died after one month to fourteen years after the ischaemic stroke. Morphological examinations involved the application of routine histological stains and immunohistochemical reactions with antibodies against human albumin, GFAP, macrophage antigen CD 68 and lectins (Ulex europaeus, Wheat Germ agglutinin and Bandeirea simplicifolia). The results showed a swelling of the endothelial cells and their invagination into the vessel lumen. Postapoplectic cavities and white matter spongiosis decreasing with increase in distance from the cavity were observed. Immunohistochemical study showed that there was no segmental immunoreactivity to lectins on the capillary wall. Immune reaction to albumin revealed protein extravasation to the rarefied brain parenchyma. Our results indicate that progressing damage of the white matter after ischaemia may be caused not only by degeneration of axons of neurones destroyed by stroke, but also by pathological changes in small blood vessels, especially in capillaries. Hence, vascular leukoencephalopathy is probably caused by arteriolar damage as well as by microangiopathy.


Venous thromboembolism in critically ill cirrhotic patients: practices of prophylaxis and incidence.
Objectives. We compared venous thromboembolism (VTE) prophylaxis practices and incidence in critically ill cirrhotic versus noncirrhotic patients and evaluated cirrhosis as a VTE risk factor. Methods. A cohort of 798 critically ill patients followed for the development of clinically detected VTE were categorized according to the diagnosis of cirrhosis. VTE prophylaxis practices and incidence were compared. Results. Seventy-five (9.4%) patients had cirrhosis with significantly higher INR (2.2 ± 0.9 versus 1.3 ± 0.6, P < 0.0001), lower platelet counts (115,000 ± 90,000 versus 258,000 ± 155,000/ μ L, P < 0.0001), and higher creatinine compared to noncirrhotic patients. Among cirrhotics, 31 patients received only mechanical prophylaxis, 24 received pharmacologic prophylaxis, and 20 did not have any prophylaxis. Cirrhotic patients were less likely to receive pharmacologic prophylaxis (odds ratio, 0.08; 95% confidence interval (CI), 0.04-0.14). VTE occurred in only two (2.7%) cirrhotic patients compared to 7.6% in noncirrhotic patients (P = 0.11). The incidence rate was 2.2 events per 1000 patient-ICU days for cirrhotic patients and 3.6 events per 1000 patient-ICU days for noncirrhotics (incidence rate ratio, 0.61; 95% CI, 0.15-2.52). On multivariate Cox regression analysis, cirrhosis was not associated with VTE risk (hazard ratio, 0.40; 95% CI, 0.10-1.67). Conclusions. In critically ill cirrhotic patients, VTE incidence did not statistically differ from that in noncirrhotic patients.


[Decrease of intestinal absorption of 47-calcium in chronic alcoholism].
Intestinal 47-calcium absorption has been studied in 34 chronic alcoholics, 17 of whom were cirrhotics (group A) and 17 non-cirrhotics (group B). These patients were compared with 44 normal subjects (group C). In group C, the 47Ca 2 h plasma % of the dose showed a significant negative correlation to the total body weight (p less than 0.001) and a positive correlation with the serum albumin (p less than 0.05). The mean intestinal absorption of 47Ca expressed as 2 h plasma % of the dose multiplied by total body weight was 131 +/- SD 52 in group A and 136 +/- SD 71 in group B. These two means are significantly low (p less than 0.001 and p less than 0.002 respectively) in relation to that found in group C (168 +/- SD 32). These results suggest that intestinal calcium absorption is diminished in chronic alcoholism even in the absence of hepatic cirrhosis.


Emerging Targets of Diuretic Therapy.
Diuretics are commonly prescribed for treatment in patients with hypertension, edema, or heart failure. Studies on hypertensive and salt-losing disorders and on urea transporters have contributed to better understanding of mechanisms of renal salt and water reabsorption and their regulation. Proteins involved in the regulatory pathways are emerging targets for diuretic and aquaretic therapy. Integrative high-throughput screening, protein structure analysis, and chemical modification have identified promising agents for preclinical testing in animals. These include WNK-SPAK inhibitors, ClC-K channel antagonists, ROMK channel antagonists, and pendrin and urea transporter inhibitors. We discuss the potential advantages and side effects of these potential diuretics.


Memory instability as a gateway to generalization.
Our present frequently resembles our past. Patterns of actions and events repeat throughout our lives like a motif. Identifying and exploiting these patterns are fundamental to many behaviours, from creating grammar to the application of skill across diverse situations. Such generalization may be dependent upon memory instability. Following their formation, memories are unstable and able to interact with one another, allowing, at least in principle, common features to be extracted. Exploiting these common features creates generalized knowledge that can be applied across varied circumstances. Memory instability explains many of the biological and behavioural conditions necessary for generalization and offers predictions for how generalization is produced.


Irreducible Dislocation of the Great Toe Interphalangeal Joint, Dorsal, and Plantar. Management and Long-term Evolution.
Irreducible dislocation of the great toe interphalangeal (IP) joint is a rare injury that has scarcely been reported in dorsal direction, but no reported in plantar direction. Closed reduction usually leads to sesamoid incarceration, making the reduction impossible. The purpose of this article is to review the management of irreducible IP dislocation of the great toe presenting three new patients who cover several forms: Open and closed dorsal Miki Type 2 dislocation and one chronic neglected plantar dislocation. These three new cases demonstrate different presentations of IP (adolescents or young adults, open or closed, acute or chronic, dorsal, and plantar). Usually, Miki's Type I is the result of a failed IP dorsal Miki's 2 dislocation reduction. Closed reduction without traction is not usually sufficient, thus percutaneous reduction with K-wire fixation or open reduction should be employed. Open reduction was required in these cases. A Kirschner wire was used to for temporal immobilization in two of the cases and a buddy strapping securing to the second toe for 3 weeks in the three cases. In dorsal dislocations the reduction must be performed without axial traction and only by pressure in the base of the phalanx. Secondary to the trial of orthopedic reduction or spontaneously, incarceration of the sesamoids bones is the rule (Miki 1). In this situation, percutaneous or open reduction must be performed. Plantar dislocation does not provoque intra-articular sesamoid interposition. This article describes the first reported case of neglected plantar dislocation that required open reduction, similar management adding that the long-term functional prognosis is good.


Use of a structured kinetic model of antibody synthesis and secretion for optimization of antibody production systems: I. Steady-state analysis.
Steady-state simulations using our previously developed structured kinetic model of antibody synthesis and secretion by hybridoma cells are used here in conjunction with factorial design analysis to identify intracellular parameters important in determining the specific antibody secretion rate and predict the dependence of this rate on cell specific growth rate. Simulation results suggest that the specific growth rate, the assembly rate of the heavy and light chains and the heavy- and -chain gene dosage can significantly affect the rate of antibody secretion. Based on these results, environmental and/or genetic manipulation approaches are proposed for maximizing the specific antibody secretion rate and the antibody volumetric productivity in large-scale antibody production systems.


Evaluation of pharmacy students' rural placement program: preparation for interprofessional practice.
To date, there are few data on pharmacy-specific placement programs and their impact on students' work after graduation. The present study evaluated an innovative rural pharmacy placement program targeted at influencing students to work and live in rural areas after graduation. A secondary aim of the study was to explore the students' intentions to come back and practice in rural areas as a result of their involvement in the rural pharmacy program. A questionnaire was distributed, by hand, to a total of 58 third and fourth (final) year pharmacy students undertaking their rural placement in the Gippsland region, in rural Victoria in 2011 and 2012. Fifty-seven responses were returned (response rate = 98%). Students stated that understanding pharmacy practice from a rural perspective, visits to rural health professionals and sites and the attitude of their preceptors were essential to their satisfaction with their rural placements. A significant number of students (72%) intend to seek employment in rural areas if opportunities arise as a result of their increased rural awareness. The key components for a successful rural placement program were described by the surveyed students as social awareness, recognising job opportunities and interprofessional learning. The evaluation of the rural placement program revealed that students valued their visits to rural sites and their interaction with other rural health professionals the most.


Patterns of change in adolescent smoking behavior and results of a one year follow-up of a smoking prevention program.
A smoking prevention program for adolescents conducted in two public middle schools focused on resisting peer pressure to smoke and understanding the intent of commercial cigarette advertising. One class in each school participated in the program group and one served as a control group. The program consisted of eight sessions and was conducted by first-year medical students. Data on smoking behavior and related information were obtained from self-administered questionnaires at baseline, at the conclusion of the program, and one year later. One year after the program was concluded, the proportion of non-smokers was higher among those who had participated in the program than among the controls. This suggests that routine implementation of smoking prevention programs in conventional school settings may be productive in reducing the prevalence of cigarette smoking.


A Systematic Review and Meta-Analysis of Mindfulness-Based (Baduanjin) Exercise for Alleviating Musculoskeletal Pain and Improving Sleep Quality in People with Chronic Diseases.
we performed the first systematic review with meta-analyses of the existing studies that examined mindfulness-based Baduanjin exercise for its therapeutic effects for individuals with musculoskeletal pain or insomnia. Both English- (PubMed, Web of Science, Elsevier, and Google Scholar) and Chinese-language (CNKI and Wangfang) electronic databases were used to search relevant articles. We used a modified PEDro scale to evaluate risk of bias across studies selected. All eligible RCTS were considered for meta-analysis. The standardized mean difference was calculated for the pooled effects to determine the magnitude of the Baduanjin intervention effect. For the moderator analysis, we performed subgroup meta-analysis for categorical variables and meta-regression for continuous variables. The aggregated result has shown a significant benefit in favour of Baduanjin at alleviating musculoskeletal pain (SMD = -0.88, 95% CI -1.02 to -0.74, p < 0.001, I² = 10.29%) and improving overall sleep quality (SMD = -0.48, 95% CI -0.95 to -0.01, p = 004, I² = 84.42%). Mindfulness-based Baduanjin exercise may be effective for alleviating musculoskeletal pain and improving overall sleep quality in people with chronic illness. Large, well-designed RCTs are needed to confirm these findings.


Apoptotic ratios and mitotic abnormalities in 17-β-estradiol-transformed human breast epithelial MCF-10F cells.
Treatment of human breast epithelial cells MCF-10F with 17-β-estradiol has been reported to result in E2-transformed cells which have given rise to highly invasive C5 cells that in turn generate tumors in SCID mice. From these tumors, various cell lines, among which C5-A6-T6 and C5-A8-T8, were obtained. Although different phases of the tumorigenesis process in this model have been studied in molecular biology and image analysis assays, no cytological data on apoptotic ratios and mitotic abnormalities have been established to accompany the various steps leading to 17-β-estradiol-treated MCF-10F cells to tumorigenesis. Here we detected that the apoptotic ratio decreases with the transformation and tumorigenesis progress, except for the tumor cell line C5-A8-T8, probably on account of its more intense proliferation rate and a more rapid culture medium consumption. Increased frequency of mitotic abnormalities contributed by triple- and tetrapolar metaphases, and by lagging chromosomes and chromosome bridges observed at the anaphase found by transformation and tumorigenesis progress. However, no difference was found under these terms when the C5-A6-T6 and C5-A8-T8 tumor cell lines were compared to each other. Present findings are in agreement with the nuclear instability and enrichment of dysregulated genes in the apoptotic process promoted by transformation and tumorigenesis in 17-β-estradiol-treated MCF-10F cells.